GEN3014 Safety Trial in Relapsed or Refractory Hematologic Malignancies

Acute Myeloid Leukemia (AML) Clinical Trial

Official title:

An Open-Label, Multicenter, Phase 1/2 Trial of GEN3014 (HexaBody®-CD38) in Relapsed or Refractory Multiple Myeloma and Other Hematologic Malignancies

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04824794
• Other study ID #: GCT3014-01
• Secondary ID: 2020-003781-40NL
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: March 9, 2021
• Est. completion date: December 31, 2026

Study information

• Verified date: June 2024
• Source: Genmab
• Contact: Genmab Trial Information
• Phone: +45 70202728
• Email: clinicaltrials[@]genmab.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The drug that will be investigated in the study is an antibody, GEN3014. Since this is the first study of GEN3014 in humans, the main purpose is to evaluate safety. Besides safety, the study will determine the recommended GEN3014 dose to be tested in a larger group of participants and assess preliminary clinical activity of GEN3014. GEN3014 will be studied in relapsed or refractory multiple myeloma (also known as RRMM) and other blood cancers. The study consists of 3 parts:

1. The Dose Escalation will test increasing doses of GEN3014 to find a safe dose level to be tested in the other two parts.

2. Expansion Part A will further test the GEN3014 dose determined from the Dose Escalation Part.

3. Expansion Part B will compare intravenous (IV) GEN3014 with the subcutaneous (SC) daratumumab in ex-US countries.

Participants will receive either GEN3014 or daratumumab; none will be given placebo. The study duration will be different for the individual participants. Overall, the study may be ongoing up to 5 years after the last participant's first treatment.

Description:

This trial will be conducted in 3 parts: Dose Escalation (phase 1), Expansion Parts, A and B (phase 2).

In the dose escalation phase GEN314 will be evaluated in RRMM and relapsed and refractory acute myeloid leukemia (R/R AML). The participants will receive GEN3014 administered at various dose levels in 28 day cycles. Dose Limiting Toxicities (DLTs) will be assessed during the first treatment cycle and the Maximum Tolerated Dose (MTD) and/or Recommended phase 2 dose (RP2D) will be determined.

In Expansion Part A, GEN3014 will be further evaluated in 4 cohorts: anti-CD38 monoclonal antibody (mAb)-naive RRMM, anti-CD38 mAb-refractory RRMM, relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL), and R/R AML at the RP2D identified from the Dose Escalation per protocol. In Expansion Part B, GEN3014 IV will be compared to daratumumab SC, head-to-head (H2H) to evaluate whether GEN3014 may be more potent in anti-CD38 mAb-naïve RRMM participants.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 252
• Est. completion date: December 31, 2026
• Est. primary completion date: October 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Key Inclusion Criteria

• Must have fresh bone marrow samples collected at Screening for RRMM, R/R AML, and R/R DLBCL with suspected bone marrow involvement.

• Dose Escalation phase, Expansion Part A (for MM and AML) and Expansion Part B- Eastern Cooperative Oncology Group (ECOG) performance status (PS) score 0, 1, or 2. Expansion Part A (for DLBCL): ECOG PS 0 or 1.

• Has acceptable laboratory test results during the Screening period.

• A woman of reproductive potential must agree to use adequate contraception during the trial and for 12 months after the last GEN3014 or daratumumab SC administration.

• A woman of childbearing potential must have a negative serum beta-human chorionic gonadotropin (ß-hCG) at Screening and additionally, for Expansion Part B, within 72 hours of the first dose of study treatment prior to dosing.

• A woman must agree not to donate eggs (ova, oocytes) for assisted reproduction during the trial and for 12 months after receiving the last dose of GEN3014 or daratumumab SC.

• A man who is sexually active with a woman of childbearing potential and has not had a vasectomy must agree to use a barrier method of birth control and all men must not donate sperm during the trial and for 12 months after receiving the last dose of GEN3014 or daratumumab SC.

Specific for RRMM:

• Must have documented multiple myeloma as defined by the criteria below and have evidence of disease progression on the most recent prior treatment regimen based on IMWG criteria:

• Prior documentation of monoclonal plasma cells in the bone marrow =10% or presence of a biopsy-proven plasmacytoma and,

• Measurable disease at baseline as defined by any of the following:

• Immunoglobulin (Ig) G, IgA, IgD, or IgM myeloma: Serum M-protein level =0.5 g/dL (=5 g/L) or urine M protein level =200 mg/24 hours or,

• Light chain myeloma: Serum Ig free light chain (FLC) =10 mg/dL and abnormal serum Ig kappa lambda FLC ratio.

Note: Participants with RRMM must have exhausted standard therapies, at the investigator's discretion.

• For anti-CD38 mAb-naive RRMM Cohort: Participant received at least 3 prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory imide drug (IMiD) in any order, or is double refractory to a PI and an IMiD; or participant received = 2 prior lines of therapy if 1 of those lines included a combination of PI and IMiD. Note: Participants should not have received any anti-CD38 antibody.

• Anti-CD38 mAb-naive RRMM participants will be enrolled from ex-US countries.

• Dose Escalation phase - For anti-CD38 mAb-treated RRMM Cohort: Participant has received at least 2 prior lines of therapy and must have discontinued daratumumab or isatuximab for at least 4 weeks prior to the first dose of GEN3014. Note: Participants should not have received any other anti-CD38 antibody except daratumumab or isatuximab.

Specific for R/R AML:

• Relapsed or refractory AML, both de novo or secondary; must have failed all conventional therapy. Acute promyelocytic leukemia (APL) is excluded from this trial. Note: Relapse is defined by BM blasts =5% in patients who have been in CR previously, or reappearance of blasts in the blood, or development of extramedullary AML. Refractory is defined as not being able to achieve a CR after the initial therapy.

• Participant with relapsed AML who received at least 2 prior therapies for AML with the exception of hydroxyurea.

• Participant with refractory AML who received at least 1 prior line of therapy for AML with the exception of hydroxyurea.

• Participant's life expectancy at Screening is judged to be at least 3 months.

Specific for DLBCL:

• Expansion phase: Relapsed or refractory DLBCL, both de novo or histologically transformed. Participants with R/R DLBCL must have exhausted standard therapies, at the investigator's discretion.

• Expansion phase: Received at least 2 prior lines of systemic therapy, with 1 being a CD20-containing chemoimmunotherapy.

• Expansion phase: Have at least 1 measurable site of disease as per Lugano criteria.

• Expansion phase: Must have available archival or fresh tumor tissue or both to submit to a central laboratory for CD38 assay.

Key Exclusion Criteria

• Prior treatment with any CD38-directed therapies (eg, daratumumab, isatuximab, CD38 chimeric antigen receptor T cell (CAR-T), bispecific antibody (Ab)) in anti-CD38 mAb-naive RRMM Cohort. Note: Prior daratumumab or isatuximab exposure is allowed for anti-CD38 mAb-treated RRMM participants in the Dose Escalation and anti-CD38 mAb-refractory RRMM Cohort in the Expansion Part A.

• Treatment with an anti-cancer agent, chemotherapy, radiation therapy, or major surgery within 2 weeks prior to the first dose of study treatment (Dose Escalation and Expansion Part A) or randomization (Expansion Part B).

• Treatment with an investigational drug within 4 weeks or 5 half-lives, whichever is shorter, prior to the first dose of study treatment (Dose Escalation and Expansion Part A) or randomization (Expansion Part B).

• Cumulative dose of corticosteroids more than the equivalent of =140 mg of prednisone within 2-week period before the first dose of study treatment (Dose Escalation and Expansion Part A) or maximum cumulative dose of dexamethasone 160 mg within 28 days of randomization (Expansion Part B).

• Has clinically significant cardiac disease.

• Toxicities from previous anti-cancer therapies have not resolved to baseline levels or to Grade 1 or less except for alopecia and peripheral neuropathy.

• Primary central nervous system (CNS) tumor or known CNS involvement at Screening.

• Has known history/positive serology for hepatitis B.

• Known medical history or ongoing hepatitis C infection that has not been cured.

• Known history of seropositivity of human immunodeficiency virus (HIV) (Dose Escalation and Expansion Part A) or to be positive for HIV with details in the protocol (Expansion Part B).

• Currently receiving any other investigational agents.

• A woman who is pregnant or breast-feeding, or who is planning to become pregnant while enrolled in this trial or within 12 months after the last dose of study treatment.

• A man who plans to father a child while enrolled in this trial or within 12 months after the last dose of study treatment.

Specific Exclusion Criteria for RRMM:

• Prior allogeneic hematopoietic stem cell transplant (HSCT).

• Autologous HSCT within 3 months of the first dose of GEN3014.

Specific Exclusion Criteria for R/R AML:

• <5% blasts in blood or bone marrow at Screening.

• White blood cell (WBC) counts =50,000/microliter (µL) in peripheral blood that cannot be controlled by hydroxyurea prior to the first dose of GEN3014.

• Prior autologous HSCT.

• Allogenic HSCT within 3 months of the first dose of GEN3014.

• Active graft-versus-host-disease requiring immunosuppressive treatment. Any immunosuppressive medication (eg, calcineurin inhibitors) must be stopped =4 weeks prior to the first dose of GEN3014.

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Related Conditions & MeSH terms

• Acute Myeloid Leukemia (AML)
• Diffuse Large B Cell Lymphoma (DLBCL)
• Hematologic Neoplasms
• Leukemia, Myeloid, Acute
• Lymphoma, Large B-Cell, Diffuse
• Multiple Myeloma
• Neoplasms, Plasma Cell

Intervention

Biological:
• GEN3014
GEN3014 is administered by IV infusion.

Drug:
• Daratumumab
Daratumumab is administered by SC injections.

Locations

Country	Name	City	State
Australia	Northern Health	Epping
Australia	The Alfred Hospital	Melbourne
Australia	Royal Prince Alfred Hospital	Sydney
Bosnia and Herzegovina	University Clinical Center of the Republic of the Srpska	Banja Luka
Bosnia and Herzegovina	Klinika za hematologiju KCUS	Sarajevo
Bosnia and Herzegovina	UKC - University Clinical Center Tuzla	Tuzla
Czechia	Fakultni Nemocnice Brno	Brno
Czechia	Vseobecna fakultni nemocnice	Nové Mesto
Czechia	Fakultni Nemocnice Hradec Kralove FNHK	Nový Hradec Králové
Czechia	Fakultni Nemocnice Olomouc (FNOL)	Olomouc
Czechia	FNO - Fakultni nemocnice Ostrava	Poruba
Denmark	Aalborg Universitet	Aalborg
Denmark	Vejle Hospital	Vejle
France	CHRU de Lille	Lille
France	CHRU de Nantes	Nantes
Georgia	ARENSIA Exploratory Medicine LLC	Tbilisi
Greece	Alexandra General Hospital	Athens
Greece	Evangelismos Hospital NKUA	Athens
Greece	University General Hospital of Patras	Río
Greece	Ahepa University General hospital	Thessaloníki
Hungary	Szabolcs-Szatmar-Bereg County Hospitals and University Hospital, Josa Andras University Hospital	Nyíregyháza
Korea, Republic of	Chonnam National University Hwasun Hospital	Gwangju
Korea, Republic of	Pusan National University Hospital PNUH	Pusan
Korea, Republic of	Gachon University Gil Medical Center	Seongnam
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Malaysia	Hospital Ampang	Ampang
Malaysia	Hospital Sultanah Aminah	Johor Bahru
Malaysia	Hospital Umum Sarawak	Kuching
Malaysia	Beacon Hospital	Petaling Jaya
Moldova, Republic of	Institute of Oncology, ARENSIA Exploratory Medicine	Chisinau
Netherlands	Maastricht UMC	Maastricht
Netherlands	Erasmus MC	Rotterdam
Netherlands	UMC Utrecht	Utrecht
New Zealand	Pacific Clinical Research	Auckland
New Zealand	Christchurch Hospital	Christchurch
New Zealand	Auckland Cancer Trials Centre	Grafton
New Zealand	Palmerston North Hospital	Palmerston North
North Macedonia	University Clinic of Hematology	Skopje
Philippines	Makati Medical Center	Makati City
Poland	University Centrum Kliniczne	Gdansk
Poland	Pratia Onkologia Katowice	Katowice
Poland	Pratia MCM	Kraków
Poland	Wroclaw Medical University	Wroclaw
Spain	University of Navarra	Pamplona
Spain	University Hospital of Salamanca	Salamanca
Sweden	Karolinska Institute	Huddinge
Sweden	Universitetssjukhuset i Lund	Lund
Ukraine	Arensia Exploratory Medicine	Kyiv
United States	University Hospitals Cleveland Medical Center	Cleveland	Ohio
United States	John Theurer Cancer Center	Hackensack	New Jersey
United States	Medical college of Wisconsin	Milwaukee	Wisconsin

Sponsors (1)

Lead Sponsor	Collaborator
Genmab

Countries where clinical trial is conducted

United States,  Australia,  Bosnia and Herzegovina,  Czechia,  Denmark,  France,  Georgia,  Greece,  Hungary,  Korea, Republic of,  Malaysia,  Moldova, Republic of,  Netherlands,  New Zealand,  North Macedonia,  Philippines,  Poland,  Spain,  Sweden,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Dose Escalation: Number of Participants with Dose Limiting Toxicities (DLTs)	To determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) to be studied in the Expansion part. DLT will be graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0.	Up to 28 days during the first cycle
Primary	Dose Escalation: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)		From first dose until the end of the safety follow-up period (30 days after last dose)
Primary	Expansion Part A: Objective Response Rate (ORR) of GEN3014	ORR is defined as the percentage of participants with a partial response (PR), or better based on International Myeloma Working Group (IMWG) criteria for MM participants, based on Lugano criteria for DLBCL participants, and based on International Working Group (IWG) response criteria for AML participants.	Up to 8 years
Primary	Expansion Part B: Objective Response Rate (ORR) of GEN3014 IV vs Daratumumab SC in Anti-CD38 mAb-naive RRMM Participants	ORR is defined as the percentage of participants with a PR, or better based on IMWG criteria.	Up to 8 years
Secondary	Dose Escalation: Maximum (peak) Plasma Concentration (Cmax) of GEN3014		Predose and postdose at multiple timepoints up to Cycle 6 (Cycle length=28 days); Pre-dose and 5 minutes post end of infusion from Cycle 7 and beyond (Up to 8 years)
Secondary	Dose Escalation: Time to Reach Cmax (Tmax) of GEN3014		Predose and postdose at multiple timepoints up to Cycle 6 (Cycle length=28 days); Pre-dose and 5 minutes post end of infusion from Cycle 7 and beyond (Up to 8 years)
Secondary	Dose Escalation: Pre-dose (trough) Concentrations (Ctrough) of GEN3014		Predose and postdose at multiple timepoints of each Cycle (Cycle length=28 days)
Secondary	Dose Escalation: Area Under the Concentration Time Curve From Zero to Last Quantifiable Sample (AUC0-last)		Predose and postdose at multiple timepoints up to Cycle 6 (Cycle length=28 days); Pre-dose and 5 minutes post end of infusion from Cycle 7 and beyond (Up to 8 years)
Secondary	Dose Escalation: Area Under the Concentration Time Curve From Zero to 168 hours (AUC0-168 h)		Predose and postdose at multiple timepoints up to Cycle 6 (Cycle length=28 days); Pre-dose and 5 minutes post end of infusion from Cycle 7 and beyond (Up to 8 years)
Secondary	Dose Escalation: Accumulation Ratio in Cmax (RA, Cmax)		Predose and postdose at multiple timepoints up to Cycle 6 (Cycle length=28 days); Pre-dose and 5 minutes post end of infusion from Cycle 7 and beyond (Up to 8 years)
Secondary	Dose Escalation: Accumulation Ratio in AUC (RA, AUC)		Predose and postdose at multiple timepoints up to Cycle 6 (Cycle length=28 days); Pre-dose and 5 minutes post end of infusion from Cycle 7 and beyond (Up to 8 years)
Secondary	Dose Escalation: Number of Participants with Anti-Drug Antibody (ADA) of GEN3014		From first dose until treatment discontinuation (Up to 8 years)
Secondary	Dose Escalation: Objective Response Rate (ORR) of GEN3014	ORR is defined as the percentage of participants with a PR or better based on IMWG criteria for MM participants, and based on IWG response criteria for AML participants.	Up to 8 years
Secondary	Dose Escalation: Clinical Benefit Rate (CBR) of GEN3014	CBR was determined by the investigator according to the IMWG response criteria for MM participants.	Up to 8 years
Secondary	Dose Escalation: Duration of Response (DOR) of GEN3014	DOR is defined as time from first response (PR or better) to time of disease progression or death (due to any cause), whichever comes first based on IMWG criteria for MM participants and based on IWG response criteria for AML participants.	Up to 8 years
Secondary	Dose Escalation: Time-to-response (TTR) of GEN3014	TTR is defined as the time from date of first dose to time of response (PR or better) based on IMWG criteria for MM participants and based on IWG response criteria for AML participants.	Up to 8 years
Secondary	Dose Escalation: Progression-free survival (PFS) of GEN3014	PFS is defined as the time from the date of the first dose to the date of progression or death (due to any cause), whichever comes first based on IMWG criteria for MM participants and based on IWG response criteria for AML participants.	Up to 8 years
Secondary	Dose Escalation: Overall Survival (OS) of GEN3014	OS is defined as the time from the date of first dose to the date of death due to any cause.	Up to 8 years
Secondary	Expansion Part A: Clinical Benefit Rate (CBR) of GEN3014	CBR was determined by the investigator according to the IMWG response criteria for MM participants.	Up to 8 years
Secondary	Expansion Part A: Duration of Response (DOR) of GEN3014	DOR is defined as time from first response (PR or better) to time of disease progression or death (due to any cause), whichever comes first based on IMWG criteria for MM participants, based on Lugano criteria for DLBCL participants, and based on IWG response criteria for AML participants.	Up to 8 years
Secondary	Expansion Part A: Time-to-response (TTR) of GEN3014	TTR is defined as the time from date of first dose to time of response (PR or better) for MM participants, based on Lugano criteria for DLBCL participants, and based on IWG response criteria for AML participants.	Up to 8 years
Secondary	Expansion Part A: Progression-free survival (PFS) of GEN3014	PFS is defined as the time from the date of the first dose to the date of progression or death (due to any cause), whichever comes first based on IMWG criteria for MM participants, based on Lugano criteria for DLBCL participants, and based on IWG response criteria for AML participants.	Up to 8 years
Secondary	Expansion Part A: Overall Survival (OS) of GEN3014	OS is defined as the time from the date of first dose to the date of death due to any cause.	Up to 8 years
Secondary	Expansion Part A: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) per CTCAE Version 5.0		From first dose until the end of the safety follow-up period (30 days after last dose)
Secondary	Expansion Part A: Number of Participants with Anti-Drug Antibody (ADA) of GEN3014		From first dose until treatment discontinuation (Up to 8 years)
Secondary	Expansion Part A: Maximum (peak) Plasma Concentration (Cmax) of GEN3014		Predose and postdose at multiple timepoints up to Cycle 6 (Cycle length=28 days); Pre-dose and 5 minutes post end of infusion from Cycle 7 and beyond (Up to 8 years)
Secondary	Expansion Part A: Time to Reach Cmax (Tmax) of GEN3014		Predose and postdose at multiple timepoints up to Cycle 6 (Cycle length=28 days); Pre-dose and 5 minutes post end of infusion from Cycle 7 and beyond (Up to 8 years)
Secondary	Expansion Part A: Pre-dose (trough) Concentrations (Ctrough) of GEN3014		Predose and postdose at multiple timepoints of each Cycle (Cycle length=28 days)
Secondary	Expansion Part A: Area Under the Concentration Time Curve From Zero to Last Quantifiable Sample (AUC0-last)		Predose and postdose at multiple timepoints up to Cycle 6 (Cycle length=28 days); Pre-dose and 5 minutes post end of infusion from Cycle 7 and beyond (Up to 8 years)
Secondary	Expansion Part A: Area Under the Concentration Time Curve From Zero to 168 hours (AUC0-168 h)		Predose and postdose at multiple timepoints up to Cycle 6 (Cycle length=28 days); Pre-dose and 5 minutes post end of infusion from Cycle 7 and beyond (Up to 8 years)
Secondary	Expansion Part A: Accumulation Ratio in Cmax (RA, Cmax)		Predose and postdose at multiple timepoints up to Cycle 6 (Cycle length=28 days); Pre-dose and 5 minutes post end of infusion from Cycle 7 and beyond (Up to 8 years)
Secondary	Expansion Part A: Accumulation Ratio in AUC (RA, AUC)		Predose and postdose at multiple timepoints up to Cycle 6 (Cycle length=28 days); Pre-dose and 5 minutes post end of infusion from Cycle 7 and beyond (Up to 8 years)
Secondary	Expansion Part A: Accumulation Ratio in Ctrough (RA,Ctrough)		Predose and postdose at multiple timepoints up to Cycle 6 (Cycle length=28 days); Pre-dose and 5 minutes post end of infusion from Cycle 7 and beyond (Up to 8 years)
Secondary	Expansion Part B: Ctrough Levels of GEN3014 IV or Daratumumab SC on Cycle 3 Day 1		Cycle 3 Day 1
Secondary	Expansion Part B: Very Good Partial Response (VGPR), or better of GEN3014 IV vs Daratumumab SC		Up to 8 years
Secondary	Expansion Part B: Complete Response (CR) or better of GEN3014 IV vs Daratumumab SC		Up to 8 years
Secondary	Expansion Part B: Duration of Response (DOR) of GEN3014 IV vs Daratumumab SC	DOR is defined as time from first response (PR or better) to time of disease progression or death (due to any cause), whichever comes first based on IMWG criteria for MM participants.	Up to 8 years
Secondary	Expansion Part B: Time-to-response (TTR) of GEN3014 IV vs Daratumumab SC	TTR is defined as the time from date of randomization, to time of response (PR or better) based on IMWG criteria for MM participants.	Up to 8 years
Secondary	Expansion Part B: Progression-free Survival (PFS) of GEN3014 IV vs Daratumumab SC	PFS is defined as the time from date of randomization to the date of progression or death (due to any cause), whichever comes first based on IMWG criteria for MM participants.	Up to 8 years
Secondary	Expansion Part B: Overall Survival (OS) of GEN3014 IV vs Daratumumab SC	OS is defined as the time from date of randomization to the date of death due to any cause.	Up to 8 years
Secondary	Expansion Part B: Time to Next Therapy (TTNT)	Time to next therapy (TTNT) for participants in the Expansion Part B is defined as the time from date of randomization to the start of subsequent anti-cancer therapy.	Up to 8 years
Secondary	Expansion Part B: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) per CTCAE Version 5.0		From first dose until the end of the safety follow-up period (30 days after last dose)
Secondary	Expansion Part B: Number of Participants with Anti-Drug Antibody (ADA) of GEN3014, Anti-daratumumab Antibodies and Anti-recombinant Human Hyaluronidase PH20 (rHuPH20)		From first dose until treatment discontinuation (Up to 8 years)